Sickle cell disease (SCD) is a group of widespread single-gene disorders and represents a significant public health burden worldwide. In the United States, most individuals with SCD are of African or Hispanic ancestry, groups often affected by healthcare disparities. Increased hemolysis of the fragile ?sickle? shaped erythrocytes (red blood cells), is characteristic of SCD. These red cells are destroyed and continuously removed from the circulation. Associated with a resultant increase of red blood cell production are two energy consuming events, 1. faster protein synthesis and 2. increased protein catabolism. The increased protein metabolism results in abnormally high resting energy expenditure (REE). This evidence suggests that patients with SCD require more dietary protein and energy than individuals without the disease. However, to date the use of nutritional supplementation for addressing these complications, is not adequately researched, and there are no recommended dietary allowances for SCD. We have successfully conducted a pilot randomized placebo- controlled supplementation trial in children with sickle cell anemia (SCA, who inherit two S alleles), aged 6 to 12 years. We used a nutritional formula designed to replace established nutrient shortages (including calorie consumption and essential amino acids with anti-inflammatory effects). The results show that plasma amino acid levels increased (e.g., L-Arginine by ~38%), lean body mass improved by 11%, bone mineral content by 14% and bone mineral density by 6%. REE was reduced by 18%. Based on these findings, we hypothesize that dietary protein and energy supplements will provide the extra nutrients known to be deficient in individuals with SCA. These supplements will promote tissue repair and lean body mass accretion, and improve the clinical condition of individuals with SCA. The aims of this proposal are to 1a) conduct a larger clinical trial to validate the effect of the nutritional supplement and its use for normalizing body mass, REE, protein metabolism and inflammation, over six months, in children with SCD and 1b) Conduct a robust compliance assessment intervention as a vital part of the study. New innovative therapies are needed to treat SCD. A cost-effective self-administered non-toxic nutritional treatment should be made available. This dietary approach could complement the standard patient care and therefore address both nutritional and hematological issues in tandem. Nutritional intervention (food supplementation) is virtually non-toxic and, early implementation could prevent characteristic under-nutrition in individuals with SCD, who can be at risk even prenatally.